Studies have been initiated to evaluate the prechronic toxicity of arsine gas via inhalation. Fischer 344 rats, B6C3F1 and C57BL/6 mice, and golden hamsters have been exposed to arsine gas at concentrations of between 10-5000 ppb for 14, 28, or 90 days. All groups exposed to 10 ppm or higher experienced 100% mortality within 4 days while those exposed to 5 pm showed no overt signs of toxicity. A dose-dependent increase in spleen weights and a slight increase in liver weights was observed at necropsy. Microscopic examination of spleens from exposed rats showed sequestration of erythrocytes within the red pulp, hemosiderin accumulation within macrophages, and increased erythropoiesis. Blood samples showed small decreases in packed cell volume (PCV) and a marked increase in ALAD activity. Urine samples showed elevated levels of coproporphyrin and 7 and 8 carboxyl uroporphyrin isomers. Female rats appeared less sensitive than male rats in the 14-day studies. The data suggest that alterations in the heme biosynthetic pathway may be used as early biological indicators of ongoing arsine toxicity to the hematopoietic system. These data were also correlated with complete blood cell analyses which demonstrated decreased RBC count, hemoglobin concentration and PCV. Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and platelet count were also increased. Marked polychromasia, mild to moderate anisocytosis and poikilocytosis, an increased number of Howell-Jolly bodies and nucleated red blood cells, and reticulocytosis were observed. The above observations were consistent with an arsine-induced regenerative anemia. Although the data from these studies disclosed common hematologic responses for the two species, the changes were more severe in mice than rats.